1. Field of the Invention
The invention relates to the transdermal delivery of drugs, particularly in connection with patch systems which allow for the variable dosage and/or multiple dosage of medicament in a patient controllable or pre-set format.
2. Description of the Related Art
Transdermal drug administration has recently come to the forefront as a useful route for continuous dosing of useful drugs where other means of administration are either discon-tinuous, labor intensive or where other routes present absorption or inactivation problems. Skin drugs which are administered through the skin are not subject to liver metabolism. Per os administration has been time honored i.e. "a teaspoonful three times a day". Such unit dose administration, however, is subject to the first pass liver metabolism, non-uniform absorption from the gut due to other gut contents or inactivation of the drug actives by the digestion process. This leads to erratic blood levels of the actives. In addition, the need for active periodic administration i.e. three times a day, required active and willing participation by the patient or in home or hospital settings by the caregiver. Due to the afore-mentioned disadvantages and, last but not least, due to its non- invasive character, transdermal administration has recently become very popular.
The shortcomings of invasive and metabolised drug administration are obviated by transdermal application where possible, of the drugs. A patch is adhered to a clear area of the skin and the drug is continually absorbed through the skin into the bloodstream for systemic distribution.
Selectable and variable dosage transdermal administration has been proposed in several of our copending applications. For instance, the parent of this application, entitled "A Multidose Transdermal Patch Assembly" pertains to trans-dermal medication assemblies and more particularly to such assemblies consisting of multiple unit-dose reservoirs with each reservoir having individual tear and release resealable closure means for initiation and administration of the medication. The transdermal delivery of high molecular weight drugs, as for instance insulin or calcitonin, is disclosed therein.
The upper layer of the epidermis (stratum corneum) was previously considered an impenetrable barrier in terms of drug delivery. The advent of skin enhancers has vastly improved the administration of low molecular weight drugs.
It has not been possible heretofore, however, to administer heavy molecules such as, for instance, insulin and calcitonin, i.e. not to any therapeutical level. A skin enhancement system and system adsorption theory are explained in more detail in the enclosed FIG. 14, in conjunction with the corresponding description.
The skin is particularly useful as it presents large areas for drug administration, as the skin is the largest organ of the body. The utility of such a mode of administration has been promoted with the discovery and development of a group of compounds that promote transdermal penetration of the various active drugs. Such compounds are known in the art as penetration enhancers or skin enhancers. They are generally characterized to be from the group of monovalent branched or unbranched aliphatic, cycloaliphatic or aromatic alcohols of 4-12 carbon atoms; cycloaliphatic or aromatic aldehydes or ketones of 4-10 carbon atoms, cycloalkanoyl amides of C 10-20 carbons, aliphatic, cycloaliphatic and aromatic esters, N,N-di-lower alkylsulfoxides, unsaturated oils, terpenes and glycol silicates.
These compounds and their specific activity as penetration enhancers, are more fully discussed in the text "Transdermal Delivery of Drugs, A. F. Kydonieus (ED) 1987 CRL Press and in such U.S. Patents as U.S. Pat. Nos. 4,913,905, 4,917,676 and 5,032,403.
As a result of these penetration enhancers, almost any drug, to some degree, can be administrated transdermally cf. U.S. Pat. Nos. 4,917,676, 3,598,122; 3,598,123; 3,742,951; 3,797,494; 3,948,254; 3,996,734; 4,284,444; and 4,597,961. Examples of such pharmacological actives include administra-tion of antibacterial such as the penicillins, tetracyclines, second and third generation cephalosporins, chloramphenicol sulfonamides; sedatives and/or hypnotics, such as barbitu-rates, carbromal, antitussives such as codeine and dextro-methorphan; anti-anxiety drugs such as the benzodiazepines including diazepam, buspirone; psychostimulants such as imipramine, amitriptyline and other tricyclic antidepressants; anti psychotic drugs and tran-quilizers such as lithium, chlorpromazine and haloperidol, reserpine, thiopropazate; Parkinsonism control agents such as bromotriptine, percolide, the anticholinergics including benzotropine, procyclidine, amantadine (also an antiviral); hormones and hormone antagonists and agonists, including adrenocorticosteroids; insulin, androgenic steroids, estrogenic and pro-gestrogenic steroids, thyroxin and its agonist 5-FU(fluorouracil), tamoxifen; antipyretics and analgesics such as aspirin/acetaminophen and other non-steroidal anti-inflammatory drugs (NSAID), analgesics based on morphine; morphine antagonists; vasodilating agents such as nitroglycerine, isorbide dinitrate; alpha and beta-blockers and other cardioactive drugs; antimalarials; antihistamines and anticholinergics including atropine, hyoscyamine or methscopalomine (for motion sickness); weaning agents such as nicotine (for tobacco addiction); and antiasthmatic bronchodilators such as formoterol; and combinations of such pharmaceutical actives.
Of course, while feasible, not all of these actives have yet been completely tested for efficacy by transdermal adminis-tration but many are under vigorous scrutiny. Other actives at this time are not economically viable for such administra-tion, as the cost of full safety testing is too great for the specific number of patients involved. The last paragraph of this specification, lists a number of promising drugs which are currently under intense scrutiny by us.
It is noted, in particular, that high molecular weight drugs have not yet been reported in the art as candidates for successful transdermal penetration. Emphasis is placed, in the context of this disclosure, on insulin and calcitonin. The latter hormone is a dotriacontapeptide which was first discovered in 1962. Calcintonins, originally found in and isolated from the thyroid gland of the hog, have meanwhile been synthesized in various forms. Generally, seven genuine hormones are listed under the names Hog, Man, Beef, Salmon, Sheep, Chicken, Eel and Rat, in accordance with their origin. The therapeutic use of calcitonins (particularly synthesized calcitonins) is widely reported. Due to their high molecular weight (in the vicinity of 6000 daltons), it has not been possible to transdermally administer the same.